Project Summary/Abstract Emerging hypotheses, based primarily on data from animal studies, suggest that obesity and type 2 diabetes epidemics could be due, in part, to chemical exposures during the most sensitive and vulnerable windows of development, mainly in utero. Our overarching aims are to systematically investigate the interplay of maternal heavy metal exposures, including mercury (Hg), lead (Pb), cadmium (Cd), manganese (Mn), and selenium (Se), and maternal vitamin B status in relation to placental pathology and childhood cardiometabolic outcomes using a life course framework. This proposal in motivated by the fact that exposures to these metals are ubiquitous in the general U.S. population. More alarmingly, these metals are detectable in more than 85%-99% of pregnant women, coupled with placental and fetal accumulation, posing a threat to the developing fetus. However, critical research gaps remain on our understanding of the effects of in utero exposure to these metals on the placenta and cardiometabolic risk later in life. We propose to conduct a prospective birth cohort study to examine inter-relationships between in utero exposure to heavy metals and B vitamin status (folate, B12 and homocysteine), and placenta and child cardiometabolic outcomes using a life course framework. We will leverage the exceptional database of the Boston Birth Cohort (BBC), a large, U.S. urban, predominantly low-income minority population with a high rates of maternal and child obesity and hypertension, and prevalent exposure to these metals. We will analyze ~2,000 mother-child pairs of the BBC who have postnatal follow-up data (molecular, epidemiological, clinical and nutritional databases), along with prenatal metal exposures, as assessed in maternal red blood cells. In Aim 1, we will evaluate in utero exposure to metals and cardiometabolic outcomes in childhood; in Aim 2, we will assess in utero exposure to metals and placental pathology findings; and in Aim 3, we will explore if adequate maternal folate status can mitigate the adverse effects of metal exposure. To ensure the successful implementation of this project, we have assembled an outstanding research team comprised of well- established researchers with complementary expertise in relative multi-disciplinary fields. The proposed study is innovative by bridging disciplines and developmental stages to investigate the potential pathways from prenatal exposure to metals, to placental pathology, and to childhood cardiometabolic outcomes. This study will be conducted in a sample of socioeconomically-disadvantaged minority women and children. Findings from this study are directly relevant to reduce health disparities in the most vulnerable U.S. populations, and to break the inter-generational amplification of obesity and type 2 diabetes epidemics within these populations.